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Purpose: This study aimed to determine the probability and risk factors for developing a corneal inflammatory event (CIE) during daily wear of lotrafilcon A silicone hydrogel contact lenses.

Methods: Eligible participants (n = 218) were fit with lotrafilcon A lenses for daily wear and followed up for 12 months. Participants were randomized to either a polyhexamethylene biguanide-preserved multipurpose solution or a one-step peroxide disinfection system. The main exposures of interest were bacterial contamination of lenses, cases, lid margins, and ocular surface. Kaplan-Meier (KM) plots were used to estimate the cumulative unadjusted probability of remaining free from a CIE, and multivariate Cox proportional hazards regression was used to model the hazard of experiencing a CIE.

Results: The KM unadjusted cumulative probability of remaining free from a CIE for both lens care groups combined was 92.3% (95% confidence interval [CI], 88.1 to 96.5%). There was one participant with microbial keratitis, five participants with asymptomatic infiltrates, and seven participants with contact lens peripheral ulcers, providing KM survival estimates of 92.8% (95% CI, 88.6 to 96.9%) and 98.1% (95% CI, 95.8 to 100.0%) for remaining free from noninfectious and symptomatic CIEs, respectively. The presence of substantial (>100 colony-forming units) coagulase-negative staphylococci bioburden on lid margins was associated with about a five-fold increased risk for the development of a CIE (p = 0.04).

Conclusions: The probability of experiencing a CIE during daily wear of lotrafilcon A contact lenses is low, and symptomatic CIEs are rare. Patient factors, such as high levels of bacterial bioburden on lid margins, contribute to the development of noninfectious CIEs during daily wear of silicone hydrogel lenses.

Contact lens–related corneal inflammatory events (CIEs) can range from asymptomatic microinfiltrates to severe symptomatic events disrupting activities of daily living. Efron and Morgan1 have advanced the concept that all contact lens–related corneal infiltrates are “CIEs,” including severe microbial keratitis (MK), and thus, all should be graded on a continuous spectrum of disease severity. Although the incidence, prevalence, and risk factors for infectious keratitis have been well documented across all modalities of contact lens wear, the same is not true for the more common contact lens–related CIEs.

The published literature tells us that the prevalence of asymptomatic CIEs in non–contact lens wearers ranges from 1.6 to 4%,2,3 and their presence may signify a normal response to the local ocular environment. Silicone hydrogel lenses double the risk of CIEs compared to their lower Dk counterparts.4–8 During extended wear with silicone hydrogel lenses, the incidence of symptomatic CIEs is 2.5 to ∼6% per year.9–12 When asymptomatic CIEs are included, the rates range from ∼6 to 26% per year, although these events are often only observed with frequent follow-up.8,13,14 Lastly, extended wear use of contact lenses significantly increases the risk of CIEs,5–7,15 but there are very few prospective studies that provide the incidence of CIEs during daily wear, especially with silicone hydrogel lenses.

Recently, two large multicenter retrospective chart review studies by Chalmers et al.4,6 reported the incidence of CIEs that presented for eyecare in optometry school clinics (i.e., symptomatic CIEs) across multiple lens types and wear schedules (although predominantly daily wear). The incidence was just more than 3% per year after reviewing records from 6117 patient-years of lens wear.4,6 In 2009, Carnt et al.16 assessed the daily wear CIE rate in a series of short-term (3 months) nonrandomized prospective clinical trials where 558 participants participated in one or more studies using specific combinations of silicone hydrogel lenses and lens care products. The CIE rate was ∼20% when annualized to 1 year, but the rate varied widely by solution brand and lens material.16

Some studies have cultured organisms from CIE lesions that have often been presumed to be sterile.17,18 Contact lens–related CIEs have been attributed to hypersensitivity responses to bacteria or their toxins, preservatives and preservative toxicity, postlens debris, hypoxia, and acute or self-limiting microbial infections.17,19 It has been well documented that CIEs are associated with bacterial adhesion to lenses.14,20–25 In fact, adhesion of planktonic bacterial cells is higher on some silicone hydrogel lenses compared to traditional hydrogel lenses,26–28 which may explain the higher rate of CIEs observed in silicone hydrogel lens wear. Some of the more symptomatic CIEs, such as contact lens–induced acute red eye and infiltrative keratitis, are associated with bacteria that are not part of the normal ocular microbiota.20–24 For example, carriers of gram-negative bacteria on lenses are five times more likely to develop contact lens–induced acute red eye.25 However, normal ocular flora has also been associated with some less severe CIEs. For example, carriers of gram-positive bacteria on lenses, particularly coagulase-negative staphylococci (CNS) or Corynebacterium spp., are approximately three and eight times more likely to develop contact lens–induced peripheral ulcers (CLPUs) and asymptomatic infiltrates (AIs), respectively.25

The Daily Wear Corneal Infiltrative Event (DWCIE) Study was conceived to determine the cumulative annual probability of developing a CIE during silicone hydrogel lens daily wear. It builds on the results and method of the Longitudinal Analysis of Silicone Hydrogel (LASH) Contact Lens Study that provided annual incidence and risk factors for CIE development during silicone hydrogel extended wear. The LASH Study controlled lens type (lotrafilcon A) and assessed microbial contamination of lenses and the ocular surface in 205 participants for 12 months of continuous wear. Substantial bacterial bioburden on study lenses was a major risk factor for the development of a CIE, rendering a patient more than 800% more susceptible to developing a CIE over time.14 As in the LASH Study, a single lens type (lotrafilcon A) is used in the DWCIE Study to allow direct comparisons between microbial lens contamination in daily wear versus extended wear as a risk factor for CIE development. In summary, the DWCIE Study, described herein, explores which risk factors, in particular microbial contamination of lotrafilcon A lenses, cases, and ocular surface, contribute to the development of a CIE for 12 months of daily wear.

METHODS

DWCIE Study Cohort and Design

The DWCIE Study was a prospective, investigator-masked cohort study, with an embedded randomized clinical trial of solution use. Participants fit to the Air Optix Aqua Night & Day Lens (lotrafilcon A; Alcon/Ciba Vision, Duluth, GA) for up to 30 days of daily wear with monthly disposal were followed up for 1 year at the University Hospitals Eye Institute, part of the University Hospitals Case Medical Center and the Department of Ophthalmology and Visual Sciences at Case Western Reserve University, Cleveland, OH. All participants signed a written informed consent before participation. The study was approved by the University Hospitals Case Medical Center Institutional Review Board and followed all the Tenets of the Declaration of Helsinki. Subject demographics are listed in Table 1.

At the baseline visit, the enrolled participants were block randomized to one of two solutions for use with the lotrafilcon A lenses: a preserved multipurpose (MPS) solution (Renu Multiplus; relabeled “Renu fresh multipurpose solution” in December 2009; Bausch & Lomb, Rochester, NY) or a one-step hydrogen peroxide care system (Clear Care; Alcon/Ciba Vision) using rub and rinse regimens. Patients were stratified by the presence or absence of previous contact lens–related adverse events. Within each group, balanced block randomization with random block size (6, 8, or 10) was used to assign participants to MPS or peroxide. Investigators having clinical interactions or obtaining study data were masked to solution assignment. All participants were provided nonpreserved saline solution (Unisol 4; Alcon Laboratories, Fort Worth, TX) for the purpose of storing the lens for prompt transport to the UH Eye Institute if an adverse response precluded continued wear. The participants randomized to the peroxide system were provided additional nonpreserved saline (Unisol 4) to rinse the lenses before insertion if needed. Companion lens rewetting drops were provided to the patients for use as needed. Renu fresh participants received Renu Rewetting Drops (Bausch & Lomb) and Clear Care participants received Aquify rewetting drops (Alcon/Ciba Vision). Clear Care cases were replaced each time a new bottle of Clear Care was opened or more frequently if taken for culture. Renu cases were replaced every 3 months or more frequently if taken for culture.

Enrolled participants returned for follow-up visits after 2 weeks, and after 1, 2, 5, 8, and 12 months of daily wear, in addition to unscheduled visits as needed. At every visit, each eye was assessed for the presence of a CIE using definitions adopted from the standards as listed in the “Institute for Eye Research/L.V. Prasad Eye Institute (IER/LVPEI) Guide To Corneal Infiltrative Conditions.”

Collection and Classification of Covariates

Demographic and social covariates of interest included age, sex, refractive error, history of previous adverse events, and level of education. Ocular covariates were drawn from the affected eye at visits preceding a CIE, or any visit for event-free participants, unless otherwise noted. Efron Grading Scales29,30 were used for grading blepharitis, meibomian gland dysfunction, corneal neovascularization, epithelial microcysts, and corneal edema. The IER grading scales were used for grading upper tarsal plate redness and roughness, limbal redness, bulbar redness, and conjunctival staining. A modified version of the IER grading scale was used for corneal staining to account for staining density in each of five corneal zones, as was done in the LASH Study.14 Excessive staining as a cause for discontinuation was determined a priori and was defined as either (1) micropunctate staining in all five zones with a surface area greater than 45% and a density of at least 3 in four of five zones or (2) macropunctate or coalescent macropunctate staining in at least three of five zones with a surface area greater than 31% and a density of at least 3 in at least three of five zones. Presumed solution induced corneal staining was defined as present when micropunctate stain encompassing more than 15% surface area was present in at least four zones. Lissamine green conjunctival staining was noted to be either circumlimbal or diffuse and was graded as none, faint, or dense in each of four paralimbal zones. Tear breakup time was recorded as the time in seconds it took for the fluorescein-stained tear film to display instability. Aqueous tear production was assessed with an unstimulated, anesthetized Schirmer test.

Aerobic cultures were performed on lid margins and conjunctival surfaces at baseline and after 1, 5, and 12 months of wear. Lenses were aseptically removed and aerobically cultured after 1, 5, and 12 months of wear. Lids, conjunctivae, and contact lenses were also cultured during any adverse event or on the first visit after the development of a CLPU if diagnosed by an asymptomatic corneal scar. Methods of lid, conjunctival, and lens cultures used the same techniques as in the LASH Study.31 Briefly, the lower lid margin and the upper bulbar conjunctivae of each eye were swabbed with calcium alginate swabs and directly plated on chocolate agar plates. The lenses were aseptically removed, placed in a vial containing 1.0 mL of sterile saline, and sent to the microbiological laboratory where they were aseptically removed and placed concave side down on a chocolate agar plate and covered with 10 mL of molten agar. The transport saline was separately plated on another chocolate agar plate. Cases were collected at the 2-, 5-, 8-, and 12-month and adverse event visits. Aliquots of residual case solution were directly plated on agar plates. The inside wells (and baskets in Clear Care) were thoroughly swabbed with calcium alginate swabs that were dissolved in solvent, and aliquots were plated on agar plates. All agar plates were incubated in 5% CO2 for up to 5 days at 35°C.

The culture technique and definition of bacterial bioburden used in this study were the same as those used in the LASH Study.31 Briefly, bacterial bioburden was defined as “substantial” if there was presence of high levels of commensal ocular biota or organisms of low pathogenicity or any level of pathogenic organisms. The levels of CNS considered to be “substantial” varied by location. If the colony-forming unit (CFU) count of CNS cultured from the lens, conjunctiva, or transport saline was 10 or higher, it was considered substantial. If the CFU count of CNS cultured from the case or residual case fluid was 60 or higher, it was considered substantial. For the lid margin, CNS cultured at 100 CFU or more was considered substantial.

Statistical Methods

The sample size of 218 was determined using event rates from the literature and the LASH Study and the following assumptions: (1) an overall incidence of microbial contamination of contact lenses during daily wear of 40%, (2) an incidence of CIEs in the exposed (microbial contamination group) of 30%, (3) an incidence of CIEs in the unexposed group of 7%, (4) α = 0.05, and (5) power = 80%. A resultant sample size of 87 total persons was required to test the primary hypothesis per lens-solution combination, which was doubled to take into account the possible heterogeneity between the two solution groups. Lastly, the sample was increased by 25% to account for losses to follow-up and dropout.

Time-to-event analysis and logistic regression analyses were conducted. If a subject had a bilateral first event, the eye with the more severe CIE was used. Data were drawn from the eye that had the CIE at visits preceding the event, with one exception; microbiology assessments were drawn from the visits preceding the event as well as at the time of the event. For participants ending the study event-free, the covariates from the left eye were used in the analysis. Events were assumed to occur at the time of the visit in which they were detected. Only participants who remained in the study for at least 14 days and were cultured at least once since the baseline visit were used in the analyses (n = 194).

The cumulative unadjusted probability of remaining CIE-free was obtained using the Kaplan-Meier (KM) method. Univariate analyses of exploratory variables were performed using KM plots stratified by the presence or absence of demographic, clinical, and microbiological covariates. Univariate Cox proportional hazards regressions were used to determine initial assessments of risk of each covariate. The biologically plausible covariates of age, sex, and solution as well as variables found to be significant at p < 0.10 during univariate analyses were entered into multivariable Cox proportional hazards models.

In addition, person-based logistic regression was performed using all longitudinal data available for each subject. Univariate logistic regressions for the association of each covariate on the presence/absence of CIE were performed. The biologically plausible covariates of age, sex, and solution as well as variables found to be significant at p<0.10 during univariate analyses were entered into multivariable logistic regression models. All analyses were conducted using SAS version 9.2 (SAS Institute, Inc., Cary, NC) procedures.

RESULTS

Participants and CIE Incidence

From November 2009 to February 2012, 218 participants were enrolled and contributed 1358 person-visits and 158.4 person-years of follow-up; 1335 person-visits are used in the survival analyses from the included subject visits up to the event of interest. Table 1 lists the subject demographics and the distribution of each parameter within each solution group. Overall, 70 MPS participants and 69 peroxide participants completed the 12-month follow-up visit. Of the 218 enrolled participants, 18 (8%) discontinued because of an adverse event, 22 (10%) were lost to follow-up, and 39 (18%) discontinued because of other reasons (e.g., discomfort, pregnancy, relocation, time conflict).

Other Adverse Events

Other ocular adverse events that were not part of the main analysis were tallied and stratified by solution group. Across the 218 participants, there were 44 (20%) other related or possibly related adverse events fairly evenly distributed between the two solution groups with one exception. There was a significantly higher proportion of MPS participants experiencing superior epithelial arcuate lesions compared to peroxide users (6 vs. 0, respectively; p = 0.03). The most frequently encountered other related adverse events were contact lens papillary conjunctivitis (four MPS and seven peroxide participants) and abrasions or trapped foreign bodies (four MPS and three peroxide participants). Although not necessarily considered an adverse event, there was a large difference between the two solution groups in the proportion of participants experiencing worse than grade 2 corneal staining (46% of MPS participants vs. 10% of peroxide participants, p < 0.0001). One MPS subject was discontinued for excessive corneal staining.

Lens, Case, and Ocular Bioburden

The first columns in Tables 3 to 5 list the magnitude of the bacterial load, stratified by species, required for the classification of substantial bioburden when cultured from lids, lenses, and cases, respectively. Columns 2 and 3 in Tables 3 to 5 stratify the bacterial load by presence of a CIE and provide the frequency of substantial bioburden by species across all subject visits. The most frequently isolated groups were CNS and Staphylococcus aureus in both the unaffected and CIE groups. The frequency of substantial bioburden with CNS on lids and lenses in the CIE group was about double that of the non-CIE group. However, only lid bioburden revealed a significant signal in differences in CNS cultured between the CIE and unaffected groups (p = 0.0003).

The frequency of subjects with repeated contamination was calculated for each culture location. The percentage of subjects with substantial bioburden in either eye during two or more visits was 39%, 14%, 12%, 22%, and 59% for lids, conjunctivae, lenses, transport saline, and cases, respectively.

Univariate Analyses

Table 6 presents the univariate hazards for CIE by various demographic and clinical covariates of interest. Only two variables were significant at p < 0.10 for entry into the multivariate models: the presence of high levels of CNS on lids and assessment of dry eye via tear breakup time. Fig. 2 displays the KM plot for development of CIE stratified by substantial (≥100 CFU) CNS bioburden on lids. Participants who have substantial CNS lid bioburden have a relatively consistent increased cumulative incidence of a CIE compared to those who do not.

Multivariate Analyses

Table 7 presents the results of the multivariate Cox proportional hazards and logistic regressions, using the covariates found to be significant during univariate analyses as well as the biologically plausible covariates of age, sex, and solution. Because of the small number of events, the models were restricted to no more than four variables; thus, each univariately significant variable was combined individually with age, sex, and solution in multivariate models. The adjusted hazards and ORs for a CIE were significantly greater for participants harboring substantial CNS lid bioburden in both models, compared to their referents. In addition, a short tear breakup time (<8 seconds) retained significance in the multivariate Cox proportional hazards model. The association between gram-positive conjunctival bioburden and CIE in the multivariate logistic regression was very similar to the univariate analysis (p = 0.07; OR, 3.06; 95% CI, 0.92–10.21) and was not included in the final multivariate models.

DISCUSSION

The unadjusted cumulative incidence for a CIE with daily wear of lotrafilcon A lenses was approximately 7.7% after 1 year, including MK, and 7.2% excluding MK. This rate is more than twice that reported in retrospective chart review studies by Chalmers et al.,4,6 which have the capability to detect symptomatic CIEs that drive problem-oriented visits. The inclusion of asymptomatic CIEs in the DWCIE Study understandably increases the event rate over other retrospective chart reviews. Our reported CIE rate is lower than that annualized for all silicone hydrogel lenses as well as lotrafilcon A lenses in the study of Carnt et al.,16 although the most of their CIEs with lotrafilcon A lenses were symptomatic. Regional and population differences, solution interactions, and/or the reuse of patients in multiple trials in the study of Carnt et al. (which may have led to a “primed” immune response) may explain these differences. Nonetheless, the overall CIE rate we report is low, and the incidence of symptomatic CIEs (1.9%) is rare. Most importantly, the CIE incidence is much lower than that reported for this same lens type when worn for 30 nights of continuous wear. In the LASH Study, the unadjusted cumulative incidence for a CIE with extended wear of lotrafilcon A lenses was approximately 26.7% after 1 year.14 This highlights the known risk of CIE development associated with extended wear when most other factors are held constant.14

One case of MK occurred in a subject using Clear Care disinfection. The subject was away from home and could not seek prompt care when irritation developed. By the time the subject sought care, a culture-positive (Pseudomonas aeruginosa) corneal ulcer was detected and treated. It is unknown whether a lack of compliance lead to the complication, but certainly, the delay in care contributed to the morbidity of the event. All the remaining events were considered very mild. Although lotrafilcon A lenses were originally intended for 30 nights of continuous wear, this study supports the use of these lenses for daily wear via the low overall CIE rate, rare symptomatic rate, and mostly mild events.

This study did not find an association between lens bioburden and CIE development for 1 year of daily wear. We believe this finding does not exclude lens contamination as a risk factor for CIE development during daily wear. There are multiple explanations for the potential lack of association in this study. First, lenses were cultured at the time of detection of a CIE event or an incident CLPU scar, as well as during selected routine visits. Because more than 75% of the events (10 of 13 subjects) were asymptomatic and occurred between visits, the lens cultured at the routine visit in which the asymptomatic CIE was detected is not likely the lens worn during the time of initiation of the event. We were unable to retrieve the lens precisely at the time of CIE development in the majority of subjects. This is a common limitation in prospective studies where asymptomatic events drive the event rate. This differs from extended wear studies (as in the LASH Study), where symptomatic events drive the CIE rate and one is more likely to culture the lens worn at the time of CIE development. Second, if less virulent species or low numbers of organisms are associated with milder events32 such as asymptomatic CIEs then it is possible that our microbiology methods are not able to recover the organisms using traditional aerobic culture techniques. In fact, DNA sequencing based detection is being promoted over traditional clinical microbiology techniques because of the inherent detection limitations of the latter.33 Only viable aerobic bacteria or yeast were sought by culture from the study lenses by design because anaerobes have rarely been associated with contact lens–related adverse events. Furthermore, viable organisms are not required to initiate an immune response. Pearlman et al.34 have shown that microbial breakdown products, such a lipopolysaccharide found on gram-negative bacteria, can activate Toll-like receptors in the corneal epithelium and stimulate an inflammatory response in the absence of live organisms. Therefore, it is possible that nonviable organisms were present on the lens surfaces preventing isolation via traditional culture techniques. Lastly, we may not have had the power to detect an association between CIE and lens contamination because the assumptions made in carrying out the sample size calculations were not met. Specifically, the overall CIE incidence was low and much smaller than expected, as was the overall incidence of lens contamination. Only approximately 27% of subjects had at least one visit where substantial lens bioburden was detected (data not shown) compared to the 40%, which was expected.

The risk factors that this study was able to uncover are patient-based variables that unfortunately are not very modifiable. An increase in the number of CNS in lid flora is the predominant risk factor for CIE initiation of the types found in this study (CLPU and AI). Other expected ocular biota include Corynebacterium, Micrococcus, Bacillus, and Propionibacterium species35–41; however, these were not associated with CIEs. Our results suggest that CNS present on the ocular surface can initiate an immune response in contact lens wearers when found in high numbers on lid margins. Certain strains of CNS are pathogenic, such as invasive or biofilm-forming Staphylococcus epidermidis strains,42,43 which may be driving these events. However, this study is not able to distinguish which specific CNS species or strains were associated with a CIE because isolates were not routinely speciated or tested for virulence factors.

Our theory is that the responsible organisms arise from the lid, or are transferred from the hands to the lids, and then spill over onto the conjunctiva and lens. In fact, in comparison to the LASH Study where only approximately 13% of subjects had repeated episodes of substantial lid bioburden,31 this study found almost 40% of subjects had repeatedly contaminated lid margins. The daily insertion and removal of lenses and lid manipulation likely drive the increased lid bioburden reported herein during daily wear. Conjunctival bioburden and lens bioburden both showed the same trends of increased risk for CIE, and conjunctival bioburden was borderline significant in some models, which supports this theory.

Interestingly, this study did not find an association between case bioburden and CIE development. Surprisingly, the majority of subjects had repeatedly contaminated cases across visits (59%), which is likely why storage case bioburden was not identified as a risk factor. Alternatively, we speculate why more subjects did not have inflammatory events when using storage cases with high levels of commensal and pathogenic bioburdens. Of interest, 34 subjects had either grossly contaminated (>1000 CFU) lenses (n = 6) or cases (n = 28) during at least one visit with organisms such as P. aeruginosa, S. aureus, enteric bacilli and Proteus sp., yet were event-free. This speaks to the tremendous ability of the ocular defense mechanisms to protect the cornea from insult and infection. Nonetheless, storage case hygiene has been linked to contact lens–related keratitis,44 and the lack of storage case use in daily disposable wearers has been associated with fewer CIEs.5 Specifically, Stapleton et al.44 have shown that poor storage case hygiene and infrequent case replacement (less frequently than every 6 months), presumably leading to greater levels of case contamination with virulent environmental pathogens, increased risk for moderate and severe MK by 6.4× and 5.4×, respectively. The DWCIE Study does not contradict these findings because long-term follow-up of subjects with contaminated cases was not performed, cases were replaced more frequently than 6 months, and our event rate was so low. In fact, the storage case (and lenses) of our single subject with MK was grossly contaminated with P. aeruginosa. We believe that the lack of an association between storage case bioburden and less serious (non-infectious) CIEs as reported in this study reflects the types of organisms we found to be associated with the CLPU and AI subtypes of CIEs. In particular, these events are mostly associated with normal skin flora that may recontaminate a lens after disinfection and just before, or during, lens wear.

Peroxide care systems (compared to MPS care systems) have been found to be protective against CIEs by Chalmers et al.6 in a retrospective chart review and Carnt et al.16 in their series of prospective studies. However, this finding has not been consistently reported5 and was not found in the DWCIE Study. Differences between our findings and the two former studies likely stem from the fact that we are reporting on a much smaller sample of AIs compared to predominantly symptomatic CIEs reported in their studies. In fact, the gram-positive bacteria that we find associated with (predominantly asymptomatic) CIEs are frequently found in storage cases of peroxide users,45 and staphylococci are catalase-producing microbes, which can explain why peroxide users continue to experience CIEs. Interestingly, in our study, there were more CLPU events in the peroxide users compared to the MPS users. Contact lens–induced peripheral ulcers are known to be associated with gram-positive lens contamination,21,46,47 which can be initiated from the lid margins and lens handling, and perhaps not completely eradicated during disinfection as data from Willcox et al.45 suggest. Our data are in agreement with this mechanism. Alternatively, all the study-related AI events were in the MPS group. Scattered AIs as well as scattered symptomatic infiltrative keratitis have been associated with an immune response second to preservative hypersensitivity.48 Although the number of CIE events in the DWCIE Study is too small to draw any conclusions in this regard, our data are also in agreement with this trend.

The two regression approaches (Cox and logistic) yielded similar results for substantial lid bioburden, as expected when there are few events and these are evenly distributed over time, as seen in Fig. 2. The only difference was short tear breakup time, which was seen as a significant factor in Cox regression but not in the logistic model. Very few subjects were found to have a short tear breakup time (11 of 218), and 3 of them experienced a CIE driving the result found in the Cox model. However, we feel these data are not reliable due to such small numbers and believe this is an area that should be explored further before conclusions on the effect of tear film instability are drawn.

In summary, patient factors, such as high levels of bacterial bioburden on lid margins, contribute to the development of CIEs during daily wear of silicone hydrogel lenses. Tear film instability may also contribute, and this effect should be further explored. Bacterial bioburden continues to drive CIE events during daily contact lens wear, as has been found in multiple extended wear studies,5–7,15 and efforts should be directed at decreasing this risk factor to diminish contact lens–related CIEs.

ACKNOWLEDGMENTS

This work was supported by Alcon Laboratories with indirect support for laboratories and coordination from the Ohio Lions Eye Research Foundation and Research to Prevent Blindness. The clinicalTrials.gov identifier is NCT00937105.